Irak4 degraders and uses thereof

ABSTRACT

The present invention relates to a method of treating autoimmune/autoinflammatory diseases and hematological malignancies in a subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/651,202, filed Feb. 15, 2022, which claims the benefit of U.S.Provisional Appl. No. 63/149,625, filed Feb. 15, 2021 the entirety ofwhich is herein incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to methods of administering IRAK4 degrader5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound A), and uses thereof for treating autoinflammatory/autoimmunediseases and hematological malignancies.

BACKGROUND OF THE INVENTION

Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulateskey regulator proteins and degrades misfolded or abnormal proteins. UPPis central to multiple cellular processes, and if defective orimbalanced, it leads to pathogenesis of a variety of diseases. Thecovalent attachment of ubiquitin to specific protein substrates isachieved through the action of E3 ubiquitin ligases.

UPP plays a key role in the degradation of short-lived and regulatoryproteins important in a variety of basic cellular processes, includingregulation of the cell cycle, modulation of cell surface receptors andion channels, and antigen presentation. Interleukin-1receptor-associated kinase-4 (IRAK4) is a key component of themyddosome, a multiprotein complex involved in innate immunity thatmediates signaling through toll-like receptors (TLRs) and interleukin(IL)-1 receptors (Patra and Choi, Molecule 2016, 21(11):1529). The IRAK4protein is ubiquitously expressed across multiple different tissuetypes, including skin, lymphoid tissue, bone marrow, gastrointestinal(GI) tract and lung. The function of IRAK4 is dependent both on itskinase activity and on its scaffolding properties, which is required forthe assembly of the myddosome complex following TLR or IL-1R engagementand myeloid differentiation factor 88 (MyD88) activation (De Nardo etal., J. Bio. Chem. 2018, 293(39):15195; Cushing et al., J. Bio. Chem.2014, 289(15):10865). The NF-kB activation is particularly dependent onthe scaffolding function of IRAK4 and is a key driver of cellularproliferation and proinflammatory cytokine and chemokine productionmediated by myddosome activation.

There are numerous cutaneous, rheumatic, and GIautoinflammatory/autoimmune disease indications whose pathogenesisinvolves IL-1 family cytokines as well as TLR stimulation and where thepleiotropic effects of an IRAK4 degrader on these pathways can provide asignificant advantage over current treatment options. Further there aremultiple cutaneous indications where there is clinical proof of conceptfor targeting the IL-1R/TLR pathway but continued high unmet need formore effective therapeutics.

SUMMARY OF THE INVENTION

It has been found that the administration of IRAK4 degrader5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(Compound A) achieving certain pharmacokinetic parameters of thedisclosure has certain advantages in treatingautoimmune/autoinflammatory diseases and hematological malignancies. Forexample, it has been found that the no observed adverse effect level(NOAEL) in dogs, the most sensitive species, is 60 mg/kg/day, whichcorresponded to average, sex-combined, maximum observed concentration(C_(max)) in plasma and area under the concentration-time curve(AUC₀₋₂₄) values of 561 ng/mL and 11,700 ng*hr/mL, respectively forCompound A; 288 ng/mL and 6090 ng*hr/mL, respectively, for Compound B;and 265 ng/mL and 5620 ng*hr/mL, respectively, for Compound C on Day 42of the dosing phase.

Accordingly, in one embodiment of the present methods and uses, there isprovided a method of treating an autoimmune/autoinflammatory diseaseand/or a hematological malignancy, comprising administering to a patientin need thereof a therapeutically effective amount of Compound A, or apharmaceutically acceptable salt thereof, and/or composition thereof,wherein a C_(max) of Compound A in plasma is up to about 561 ng/mL.

In one embodiment of the present methods and uses, there is provided amethod of treating an autoimmune/autoinflammatory disease and/or ahematological malignancy, comprising administering to a patient in needthereof a therapeutically effective amount of Compound A, or apharmaceutically acceptable salt thereof, and/or composition thereof,wherein a C_(max) of Compound B in plasma is up to about 288 ng/mL.

In one embodiment of the present methods and uses, there is provided amethod of treating an autoimmune/autoinflammatory disease and/or ahematological malignancy, comprising administering to a patient in needthereof a therapeutically effective amount of Compound A, or apharmaceutically acceptable salt thereof, and/or composition thereof,wherein a C_(max) of Compound C in plasma is up to about 265 ng/mL.

In one embodiment of the present methods and uses, there is provided amethod of treating an autoimmune/autoinflammatory disease and/or ahematological malignancy, comprising administering to a patient in needthereof a therapeutically effective amount of Compound A, or apharmaceutically acceptable salt thereof, and/or composition thereof,wherein an AUC₀₋₂₄ of Compound A in plasma is up to about 11700ng*hr/mL.

In one embodiment of the present methods and uses, there is provided amethod of treating an autoimmune/autoinflammatory disease and/or ahematological malignancy, comprising administering to a patient in needthereof a therapeutically effective amount of Compound A, or apharmaceutically acceptable salt thereof, and/or composition thereof,wherein an AUC₀₋₂₄ of Compound B in plasma is up to about 6090 ng*hr/mL.

In one embodiment of the present methods and uses, there is provided amethod of treating an autoimmune/autoinflammatory disease and/or ahematological malignancy, comprising administering to a patient in needthereof a therapeutically effective amount of Compound A, or apharmaceutically acceptable salt thereof, and/or composition thereof,wherein an AUC₀₋₂₄ of Compound C in plasma is up to about 5620 ng*hr/mL.

In one embodiment of achieving the AUC₀₋₂₄ of Compound A, Compound B, orCompound C, Compound A is administered at a dose of about 10 mg/kg toabout 200 mg/kg, for example, Compound A is administered at a doseselected from about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg,about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, andabout 90 mg/kg.

In some embodiments, the T_(max) of Compound A is achieved in about 4hrs to about 12 hrs, for example, about 4, about 5, about 6, about 7,about 8, about 9, about 10, about 11, or about 12 hrs.

In some aspects, the autoimmune/autoinflammatory disease is selectedfrom a cutaneous, rheumatic, and gastrointestinalautoimmune/autoinflammatory disease. In some aspects, theautoimmune/autoinflammatory disease is a cutaneousautoimmune/autoinflammatory disease selected from atopic dermatitis (AD)and hidradenitis suppurativa (HS).

These and other aspects of this disclosure will be apparent uponreference to the following detailed description. To this end, variousreferences are set forth herein which describe in more detail certainbackground information and procedures and are each hereby incorporatedby reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION 1. General Description of CertainEmbodiments of the Invention

Compound A is a potent, highly selective, orally administeredheterobifunctional small molecule therapeutic targeting IRAK4 and the E3ligase CRBN to mediate the selective degradation of IRAK4 via theubiquitin-proteasome system.

Compound A is composed of a CRBN-targeting ligand and an IRAK4-targetingligand joined by a chemical linker. Compound A forms a ternary complexthrough non-covalent binding to both CRBN and IRAK4, bringing the E3ligase (CRBN) in close proximity to IRAK4, that now serves as itsneosubstrate. This proximity leads to IRAK4 ubiquitination andproteosomal degradation and eventual release of Compound A, which isthen free to mediate additional rounds of ternary complex formation andIRAK4 degradation.

In vitro and in vivo studies confirmed the ability of Compound A toselectively degrade its intended target, IRAK4, and to inhibitdownstream production of disease relevant proinflammatory cytokines andchemokines. In vitro, Compound A's ability to degrade IRAK4 acrossspecies was confirmed in a study of mouse and rat splenocytes and dog,monkey, and human PBMCs, where similar DC₅₀ values were observed acrossall species (<10 nM). Across a series of in vitro studies in humanperipheral blood mononuclear cells (PBMCs), whole blood, and OCI-LY10cells, Compound A robustly reduced IRAK4 levels, with DC₅₀ valuesconsistently in the low nM range. Multiple in vitro cytokine releaseassays confirmed Compound A's ability to inhibit TLR agonist(lipopolysaccharide and R848) and IL-1β-induced proinflammatory cytokineproduction (including IL-6, TNF-α, granulocyte-macrophagecolony-stimulating factor, and IL-8) in PBMCs with IC50 values also inthe low nM range. Lastly, mass spectrometry (MS) proteomic analysis ofPBMCs treated with Compound A demonstrated the compound's selectivityfor its target, with IRAK4 being the only protein degraded of more than9,000 proteins sampled.

In vivo, murine models of inflammation demonstrated the ability ofCompound A-induced IRAK4 degradation to impact TLR- and IL-1β-mediatedTh1 and Th17 inflammation as well as neutrophil migration. In the mouseair pouch model of MSU-crystal induced (TLR 2/4-dependent) inflammation,3 days twice daily administration of Compound A at doses ranging from 30to 100 mg/kg not only significantly reduced IRAK4 levels in the spleen,but also significantly reduced the inflammatory exudate, includingreduction of neutrophils and IL-1β. Similar findings were observed inthe imiquimod psoriasis model (TLR 7/8-dependent), where administrationof Compound A resulted in dose-dependent degradation of IRAK4 in thespleen and skin associated with reduction in skin thickness as well assignificant reduction of IL-1β(p<0.0001) and IL-6 (p<0.05; 300 mg/kgonly) in the skin. Overall, efficacy was associated with achieving atleast 80% or more IRAK4 knockdown in associated tissues in the modelsystems.

In vivo pharmacokinetics (PK)/pharmacodynamics (PD) studies in mice anddogs demonstrated potent IRAK4 degradation by Compound A. In wild-typemice, a single oral dose of Compound A at 300 mg/kg resulted in nearly100% degradation of IRAK4 in the skin and approximately 66% degradationin the spleen, which was sustained for at least 48-hour post-dose. Inboth the skin and spleen, maximal PD effects were achieved after tmax ateach dose level. In dogs, 7 days of oral administration at doses up to10 mg/kg/day also led to marked reduction of IRAK4 in the skin and inPBMCs, with Compound A trough plasma concentration levels as low as 3 nMinducing >85% degradation of IRAK4 in the PBMCs and degradation belowthe limit of quantitation in the skin. Recovery of IRAK4 levels wasnoted by 96 to 168 hr following last dose in dogs, demonstrating thereversible nature of Compound A induced degradation. Together, thesestudies point to the potent, on-target, and reversible effects ofCompound A against IRAK4.

In in vivo pharmacokinetic (PK) studies conducted in rats, dogs, andmonkeys, Compound A PK was characterized by moderate to high clearance,high volume of distribution at steady state, a moderate terminalhalf-life, and low to moderate bioavailability. Compound A exhibited lowsolubility, moderate permeability, and was identified as a substrate ofP-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) invitro. Compound A was highly bound to plasma proteins across nonclinicalspecies and humans and did not significantly partition into red bloodcells. In distribution studies in rats, Compound A extensivelydistributed into tissues, but had limited penetration into the centralnervous system (CNS).

In vitro and in vivo metabolism studies showed that Compound A underwentoxidative metabolism via cytochrome P450 (CYP). An excretion studyconducted in bile duct-cannulated (BDC) rats showed negligible renalclearance of Compound A, and minor to moderate biliary and intestinalexcretion as parent drug. Metabolites generated in liver microsomes fromhumans were also detected in those from rat, dog, and monkey. In the invitro drug-drug interaction studies, Compound A demonstrated potentialtime dependent inhibition (TDI) of CYP2C19 and CYP3A4 and inhibited BCRPefflux, and therefore has the potential to be a perpetrator to sensitiveCYP2C19, CYP3A4, and BCRP substrates. Conversely, Compound A isprimarily metabolized by CYP3A4 and is substrate of P-gp and BCRP andhas the potential to be a victim when co-dosing with strong or moderateinhibitors or inducers of the enzymes.

Accordingly, in some embodiments, the present disclosure provides amethod of treating an autoimmune/autoinflammatory disease and/or ahematological malignancy, comprising administering to a patient in needthereof a therapeutically effective amount of Compound A, or apharmaceutically acceptable salt thereof, and/or composition thereof,wherein a C_(max) of Compound A in plasma is up to about 561 ng/mL.

In some embodiments, the present disclosure provides a method oftreating an autoimmune/autoinflammatory disease and/or a hematologicalmalignancy, comprising administering to a patient in need thereof atherapeutically effective amount of Compound A, or a pharmaceuticallyacceptable salt thereof, and/or composition thereof, wherein an AUC₀₋₂₄of Compound A in plasma is up to about 11700 ng*hr/mL.

In some embodiments, an autoimmune/autoinflammatory disease is selectedfrom atopic dermatitis (AD) and hidradenitis suppurativa (HS).

In the following disclosure, certain specific details are set forth inorder to provide a thorough understanding of various embodiments.However, one skilled in the art will understand that the methods anduses described herein may be practiced without these details. In otherinstances, well-known structures have not been shown or described indetail to avoid unnecessarily obscuring descriptions of the embodiments.Unless the context requires otherwise, throughout the specification andclaims which follow, the word “comprise” and variations thereof, suchas, “comprises” and “comprising” are to be construed in an open,inclusive sense, that is, as “including, but not limited to.” Further,headings provided herein are for convenience only and do not interpretthe scope or meaning of the claimed invention.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure, orcharacteristic described in connection with the embodiment is includedin at least one embodiment. Thus, the appearances of the phrases “in oneembodiment” or “in an embodiment” in various places throughout thisspecification are not necessarily all referring to the same embodiment.Furthermore, the particular features, structures, or characteristics maybe combined in any suitable manner in one or more embodiments. Also, asused in this specification and the appended claims, the singular forms“a,” “an,” and “the” include plural referents unless the content clearlydictates otherwise. It should also be noted that the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

2. Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms and abbreviations have the meaningindicated:

“Compound A” refers to IRAK4 degrader5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide,of formula:

“Compound B” refers to IRAK4 degrader5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-((S)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide,of formula:

and “Compound C” refers the IRAK4 degrader5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-((R)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide,of formula:

The molecular structure of Compound A contains three chiral centers,including two fixed/stable centers around the morphine ring (R,R) andone epimerizable chiral center (R S) resulting in the two diastereomers,(S,R,R)-Compound A and (R,R,R)-Compound A, which are designated asCompound B and Compound C, respectively. In some embodiments, Compound Ais Compound B. In some embodiments, Compound A is Compound C. In someembodiments, Compound A is a mixture of Compound B and Compound C. Insome embodiments, Compound A is an approximately 1:1 mixture of CompoundB and Compound C. Both diastereomers interconvert rapidly in vitro andin vivo. In some embodiments, Compound A, or a pharmaceuticallyacceptable salt thereof, is amorphous. In some embodiments, Compound A,or a pharmaceutically acceptable salt thereof, is in crystal form. Insome embodiments, Compound A is the hydrochloride (HCl) salt. In someembodiments, Compound A HCl salt is amorphous. In some embodiments,Compound A HCl salt is in crystal form.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisdisclosure include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

As used herein, the terms “about” or “approximately” have the meaning ofwithin 20% of a given value or range. In some embodiments, the term“about” refers to within 20%, 19%, 1⁸%, 7%1, 6%1, 5%1, 4%1, 13%1, 12%,1%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

3. Description of Exemplary Methods and Uses

In some embodiments, the present disclosure provides a method oftreating an autoimmune/autoinflammatory disease and/or a hematologicalmalignancy, comprising administering to a patient in need thereof atherapeutically effective amount of Compound A, or a pharmaceuticallyacceptable salt thereof, and/or composition thereof, wherein C_(max) ofCompound A in plasma is up to about 561 ng/mL.

In some embodiments, the present disclosure provides a method oftreating an autoimmune/autoinflammatory disease and/or a hematologicalmalignancy, comprising administering to a patient in need thereof atherapeutically effective amount of Compound A, or a pharmaceuticallyacceptable salt thereof, and/or composition thereof, wherein an AUC₀₋₂₄of Compound A in plasma is up to about 11700 ng*hr/mL.

In some embodiments, an autoimmune/autoinflammatory disease is selectedfrom atopic dermatitis (AD) and hidradenitis suppurativa (HS).

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

As used herein, a patient or subject “in need of prevention,” “in needof treatment,” or “in need thereof,” refers to one, who by the judgmentof an appropriate medical practitioner (e.g., a doctor, a nurse, or anurse practitioner in the case of humans; a veterinarian in the case ofnon-human mammals), would reasonably benefit from a given treatment ortherapy.

A “therapeutically effective amount” or “therapeutically effectivedosage” of a drug or therapeutic agent, such as Compound A, is anyamount of the drug that, when used alone or in combination with anothertherapeutic agent, protects a patient or subject against the onset of adisease, such as AD, or promotes disease regression evidenced by adecrease in severity of disease symptoms, an increase in frequency andduration of disease symptom-free periods, or a prevention of impairmentor disability due to the disease affliction. The ability of atherapeutic agent to promote disease regression can be evaluated using avariety of methods known to the skilled practitioner, such as in humansubjects during clinical trials, in animal model systems predictive ofefficacy in humans, or by assaying the activity of the agent in in vitroassays.

In preferred embodiments, a therapeutically effective amount of thedrug, such as Compound A, promotes regression to the point ofeliminating the disease. In addition, the terms “effective” and“effectiveness” with regard to a treatment includes both pharmacologicaleffectiveness and physiological safety. Pharmacological effectivenessrefers to the ability of the Compound A to treat the disease in thepatient. Physiological safety refers to the level of toxicity, or otheradverse physiological effects at the cellular, organ and/or organismlevel (adverse effects) resulting from administration of the drug.

As used herein, the terms “therapeutic benefit” or “benefit fromtherapy” refers to an improvement in one or more of overall survival,progression-free survival, partial response, complete response, andoverall response rate and can also include a decrease in severity ofdisease symptoms, an increase in frequency and duration of diseasesymptom-free periods, or a prevention of impairment or disability due tothe disease affliction.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “subject,” as used herein, has the same meaning as the term“patient”.

4. Pharmacokinetics

In some embodiments, the present disclosure provides a method ofadministering Compound A to a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount ofCompound A, or a pharmaceutically acceptable salt thereof, and/orcomposition thereof, wherein a C_(max) of up to about 561 ng/mL ofCompound A in plasma is achieved.

In some embodiments, a C_(max) of Compound A in plasma is up to about550 ng/mL. In some embodiments, a C_(max) of Compound A in plasma is upto about 500 ng/mL. In some embodiments, a C_(max) of Compound A inplasma is up to about 450 ng/mL. In some embodiments, a C_(max) ofCompound A in plasma is up to about 400 ng/mL. In some embodiments, aC_(max) of Compound A in plasma is up to about 350 ng/mL. In someembodiments, a C_(max) of Compound A in plasma is up to about 300 ng/mL.In some embodiments, a C_(max) of Compound A in plasma is up to about250 ng/mL. In some embodiments, a C_(max) of Compound A in plasma is upto about 200 ng/mL. In some embodiments, a C_(max) of Compound A inplasma is up to about 150 ng/mL. In some embodiments, a C_(max) ofCompound A in plasma is up to about 100 ng/mL.

In some embodiments, a C_(max) of Compound A in plasma is about 100ng/mL. In some embodiments, a C_(max) of Compound A in plasma is about150 ng/mL. In some embodiments, a C_(max) of Compound A in plasma isabout 200 ng/mL. In some embodiments, a C_(max) of Compound A in plasmais about 250 ng/mL. In some embodiments, a C_(max) of Compound A inplasma is about 300 ng/mL. In some embodiments, a C_(max) of Compound Ain plasma is about 350 ng/mL. In some embodiments, a C_(max) of CompoundA in plasma is about 400 ng/mL. In some embodiments, a C_(max) ofCompound A in plasma is about 450 ng/mL. In some embodiments, a C_(max)of Compound A in plasma is about 500 ng/mL. In some embodiments, aC_(max) of Compound A in plasma is about 550 ng/mL. In some embodiments,a C_(max) of Compound A in plasma is about 561 ng/mL.

In some embodiments, a C_(max) of Compound A in plasma is about 500ng/mL to about 561 ng/mL, about 450 ng/mL to about 550 ng/mL, about 400ng/mL to about 500 ng/mL, about 350 ng/mL to about 450 ng/mL, about 300ng/mL to about 400 ng/mL, about 250 ng/mL to about 350 ng/mL, about 200ng/mL to about 300 ng/mL, about 150 ng/mL to about 250 ng/mL, about 100ng/mL to about 200 ng/mL, or about 50 ng/mL to about 150 ng/mL.

In some embodiments, the present disclosure provides a method ofadministering Compound A to a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount ofCompound A, or a pharmaceutically acceptable salt thereof, and/orcomposition thereof, wherein a C_(max) of up to about 288 ng/mL ofCompound B in plasma is achieved.

In some embodiments, a C_(max) of Compound B in plasma is up to about280 ng/mL, up to about 260 ng/mL, up to about 250 ng/mL, up to about 240ng/mL, up to about 220 ng/mL, up to about 200 ng/mL, up to about 180ng/mL, up to about 160 ng/mL, up to about 150 ng/mL, up to about 140ng/mL, up to about 120 ng/mL, or up to about 100 ng/mL.

In some embodiments, a C_(max) of Compound B in plasma is about 280ng/mL, about 260 ng/mL, about 250 ng/mL, about 240 ng/mL, about 220ng/mL, about 200 ng/mL, about 180 ng/mL, about 160 ng/mL, about 150ng/mL, about 140 ng/mL, about 120 ng/mL, or about 100 ng/mL.

In some embodiments, a C_(max) of Compound B in plasma is about 260ng/mL to about 288 ng/mL, about 240 ng/mL to about 260 ng/mL, about 220ng/mL to about 240 ng/mL, about 200 ng/mL to about 220 ng/mL, about 180ng/mL to about 200 ng/mL, about 160 ng/mL to about 180 ng/mL, about 140ng/mL to about 160 ng/mL, about 120 ng/mL to about 140 ng/mL, about 100ng/mL to about 120 ng/mL, or about 80 ng/mL to about 100 ng/mL.

In some embodiments, the present disclosure provides a method ofadministering Compound A to a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount ofCompound A, or a pharmaceutically acceptable salt thereof, and/orcomposition thereof, wherein a C_(max) of up to about 265 ng/mL ofCompound C in plasma is achieved.

In some embodiments, a C_(max) of Compound C in plasma is up to about260 ng/mL, up to about 250 ng/mL, up to about 240 ng/mL, up to about 220ng/mL, up to about 200 ng/mL, up to about 180 ng/mL, up to about 160ng/mL, up to about 150 ng/mL, up to about 140 ng/mL, up to about 120ng/mL, up to about 100 ng/mL, or up to about 80 ng/mL.

In some embodiments, a C_(max) of Compound C in plasma is about 260ng/mL, about 250 ng/mL, about 240 ng/mL, about 220 ng/mL, about 200ng/mL, about 180 ng/mL, about 160 ng/mL, about 150 ng/mL, about 140ng/mL, about 120 ng/mL, about 100 ng/mL, or about 80 ng/mL.

In some embodiments, a C_(max) of Compound C in plasma is about 240ng/mL to about 265 ng/mL, about 220 ng/mL to about 240 ng/mL, about 200ng/mL to about 220 ng/mL, about 180 ng/mL to about 200 ng/mL, about 160ng/mL to about 180 ng/mL, about 140 ng/mL to about 160 ng/mL, about 120ng/mL to about 140 ng/mL, about 100 ng/mL to about 120 ng/mL, about 80ng/mL to about 100 ng/mL, or about 60 ng/mL to about 80 ng/mL.

In some embodiments, the present disclosure provides a method ofadministering Compound A to a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount ofCompound A, or a pharmaceutically acceptable salt thereof, and/orcomposition thereof, wherein an AUC₀₋₂₄ of up to about 11700 ng*hr/mL ofCompound A in plasma is achieved.

In some embodiments, an AUC₀₋₂₄ of Compound A in plasma is up to about11500 ng*h/mL, up to about 11000 ng*h/mL, up to about 10500 ng*h/mL, upto about 10000 ng*h/mL, up to about 9500 ng*h/mL, up to about 9000ng*h/mL, up to about 8500 ng*h/mL, up to about 8000 ng*h/mL, up to about7500 ng*h/mL, up to about 7000 ng*h/mL, up to about 6500 ng*h/mL, up toabout 6000 ng*h/mL, up to about 5500 ng*h/mL, up to about 5000 ng*h/mL,up to about 4500 ng*h/mL, up to about 4000 ng*h/mL, up to about 3500ng*h/mL, or up to about 3000 ng*h/mL.

In some embodiments, an AUC₀₋₂₄ of Compound A in plasma is about 3,000ng*h/mL, about 3,500 ng*h/mL, or about 4,000 ng*h/mL. In someembodiments, an AUC₀₋₂₄ of Compound A in plasma is about 5,000 ng*h/mL.In some embodiments, an AUC₀₋₂₄ of Compound A in plasma is about 5,500ng*h/mL. In some embodiments, an AUC₀₋₂₄ of Compound A in plasma isabout 6,000 ng*h/mL. In some embodiments, an AUC₀₋₂₄ of Compound A inplasma is about 6,500 ng*h/mL. In some embodiments, an AUC₀₋₂₄ ofCompound A in plasma is about 7,000 ng*h/mL. In some embodiments, anAUC₀₋₂₄ of Compound A in plasma is about 7,500 ng*h/mL. In someembodiments, an AUC₀₋₂₄ of Compound A in plasma is about 8,000 ng*h/mL.In some embodiments, an AUC₀₋₂₄ of Compound A in plasma is about 8,500ng*h/mL. In some embodiments, an AUC₀₋₂₄ of Compound A in plasma isabout 9,000 ng*h/mL. In some embodiments, an AUC₀₋₂₄ of Compound A inplasma is about 9,500 ng*h/mL. In some embodiments, an AUC₀₋₂₄ ofCompound A in plasma is about 10,000 ng*h/mL. In some embodiments, anAUC₀₋₂₄ of Compound A in plasma is about 10,500 ng*h/mL. In someembodiments, an AUC₀₋₂₄ of Compound A in plasma is about 11,000 ng*h/mL.In some embodiments, an AUC₀₋₂₄ of Compound A in plasma is about 11,500ng*h/mL. In some embodiments, an AUC₀₋₂₄ of Compound A in plasma isabout 11,700 ng*h/mL.

In some embodiments, an AUC₀₋₂₄ of Compound A in plasma is about 11,000ng*h/mL to about 11,700 ng*h/mL, about 10,000 ng*h/mL to about 11,000ng*h/mL, about 9,000 ng*h/mL to about 10,000 ng*h/mL, about 8,000ng*h/mL to about 9,000 ng*h/mL, about 7,000 ng*h/mL to about 8,000ng*h/mL, about 6,000 ng*h/mL to about 7,000 ng*h/mL, about 5,000 ng*h/mLto about 6,000 ng*h/mL, or about 4,000 ng*h/mL to about 5,000 ng*h/mL.

In some embodiments, the present disclosure provides a method ofadministering Compound A to a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount ofCompound A, or a pharmaceutically acceptable salt thereof, and/orcomposition thereof, wherein an AUC₀₋₂₄ of up to about 6090 ng*h/mL ofCompound B in plasma is achieved.

In some embodiments, an AUC₀₋₂₄ of Compound B in plasma is up to about6000 ng*h/mL, up to about 5500 ng*h/mL, up to about 5000 ng*h/mL, up toabout 4500 ng*h/mL, up to about 4000 ng*h/mL, up to about 3500 ng*h/mL,up to about 3000 ng*h/mL, up to about 2500 ng*h/mL, up to about 2000ng*h/mL, or up to about 1500 ng*h/mL.

In some embodiments, an AUC₀₋₂₄ of Compound B in plasma is about 6000ng*h/mL, about 5500 ng*h/mL, about 5000 ng*h/mL, about 4500 ng*h/mL,about 4000 ng*h/mL, about 3500 ng*h/mL, about 3000 ng*h/mL, about 2500ng*h/mL, about 2000 ng*h/mL, or about 1500 ng*h/mL.

In some embodiments, an AUC₀₋₂₄ of Compound B in plasma is about 5500ng*h/mL to about 6090 ng*h/mL, about 5000 ng*h/mL to about 5500 ng*h/mL,about 4500 ng*h/mL to about 5000 ng*h/mL, about 4000 ng*h/mL to about4500 ng*h/mL, about 3500 ng*h/mL to about 4000 ng*h/mL, about 3000ng*h/mL to about 3500 ng*h/mL, about 2500 ng*h/mL to about 3000 ng*h/mL,about 2000 ng*h/mL to about 2500 ng*h/mL, or about 1500 ng*h/mL to about2000 ng*h/mL.

In some embodiments, the present disclosure provides a method ofadministering Compound A to a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount ofCompound A, or a pharmaceutically acceptable salt thereof, and/orcomposition thereof, wherein an AUC₀₋₂₄ of up to about 5620 ng*h/mL ofCompound C in plasma is achieved.

In some embodiments, an AUC₀₋₂₄ of Compound C in plasma is up to about5500 ng*h/mL, up to about 5000 ng*h/mL, up to about 4500 ng*h/mL, up toabout 4000 ng*h/mL, up to about 3500 ng*h/mL, up to about 3000 ng*h/mL,up to about 2500 ng*h/mL, up to about 2000 ng*h/mL, or up to about 1500ng*h/mL.

In some embodiments, an AUC₀₋₂₄ of Compound C in plasma is about 5620ng*h/mL, about 5500 ng*h/mL, about 5000 ng*h/mL, about 4500 ng*h/mL,about 4000 ng*h/mL, about 3500 ng*h/mL, about 3000 ng*h/mL, about 2500ng*h/mL, about 2000 ng*h/mL, or about 1500 ng*h/mL.

In some embodiments, an AUC₀₋₂₄ of Compound C in plasma is about 5000ng*h/mL to about 5620 ng*h/mL, about 4500 ng*h/mL to about 5000 ng*h/mL,about 4000 ng*h/mL to about 4500 ng*h/mL, about 3500 ng*h/mL to about4000 ng*h/mL, about 3000 ng*h/mL to about 3500 ng*h/mL, about 2500ng*h/mL to about 3000 ng*h/mL, about 2000 ng*h/mL to about 2500 ng*h/mL,or about 1500 ng*h/mL to about 2000 ng*h/mL.

In some embodiments, the present methods and uses achieve two, three,four, five, or six of the following PK parameters:

-   -   a C_(max) of Compound A in plasma    -   a C_(max) of Compound B in plasma    -   a C_(max) of Compound C in plasma    -   an AUC₀₋₂₄ of Compound A in plasma    -   an AUC₀₋₂₄ of Compound B in plasma    -   an AUC₀₋₂₄ of Compound C in plasma        wherein each of the PK parameters is independently selected from        those as described herein.

In certain embodiments of the present methods and uses, Compound A isadministered to a patient in thereof at a dose to achieve a C_(max) ofCompound A or a therapeutically effective AUC₀₋₂₄ of Compound A. In suchembodiments, Compound A is administered at a dose of about 10 mg/kg toabout 200 mg/kg, for example, Compound A is administered at a doseselected from about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg,about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, andabout 90 mg/kg.

In some embodiments, Compound A is administered at a dose of about 20mg/kg to about 60 mg/kg. In such embodiments, Compound A is administeredat a dose of about 25 mg/kg to about 65 mg/kg. In some embodiments,Compound A is administered at a dose of about 30 mg/kg to about 70mg/kg. In some embodiments, Compound A is administered at a dose ofabout 35 mg/kg to about 75 mg/kg. In such embodiments, Compound A isadministered at a dose of about 40 mg/kg to about 80 mg/kg. In someembodiments, Compound A is administered at a dose of about 45 mg/kg toabout 85 mg/kg. In such embodiments, Compound A is administered at adose of about 50 mg/kg to about 90 mg/kg. In some embodiments, CompoundA is administered at a dose of about 55 mg/kg to about 95 mg/kg. In suchembodiments, Compound A is administered at a dose of about 60 mg/kg toabout 100 mg/kg.

In some embodiments, Compound A is administered at a dose of about 30mg/kg. In some embodiments, Compound A is administered at a dose ofabout 35 mg/kg. In some embodiments, Compound A is administered at adose of about 40 mg/kg. In some embodiments, Compound A is administeredat a dose of about 45 mg/kg. In some embodiments, Compound A isadministered at a dose of about 50 mg/kg. In some embodiments, CompoundA is administered at a dose of about 55 mg/kg. In some embodiments,Compound A is administered at a dose of about 60 mg/kg. In someembodiments, Compound A is administered at a dose of about 65 mg/kg. Insome embodiments, Compound A is administered at a dose of about 70mg/kg. In some embodiments, Compound A is administered at a dose ofabout 75 mg/kg. In some embodiments, Compound A is administered at adose of about 80 mg/kg. In some embodiments, Compound A is administeredat a dose of about 85 mg/kg. In some embodiments, Compound A isadministered at a dose of about 90 mg/kg. In some embodiments, CompoundA is administered at a dose of about 95 mg/kg. In some embodiments,Compound A is administered at a dose of about 100 mg/kg. In certainembodiments, Compound A is administered at a dose of about 60 mg/kg perdose.

In certain embodiments of the present methods and uses, the T_(max) ofCompound A is achieved in about 4 hrs to about 12 hrs, for example,about 4, about 5, about 6, about 7, about 8, about 9, about 10, about11, or about 12 hrs. In some embodiments, the T_(max) of Compound A isachieved in about 4 hrs. In some embodiments, the T_(max) of Compound Ais achieved in about 5 hrs. In some embodiments, the T_(max) of CompoundA is achieved in about 6 hrs. In some embodiments, the T_(max) ofCompound A is achieved in about 74 hrs. In some embodiments, the T_(max)of Compound A is achieved in about 8 hrs. In some embodiments, theT_(max) of Compound A is achieved in about 9 hrs. In some embodiments,the T_(max) of Compound A is achieved in about 10 hrs. In someembodiments, the T_(max) of Compound A is achieved in about 11 hrs. Insome embodiments, the T_(max) of Compound A is achieved in about 12 hrs.

In certain embodiments of the present methods and uses, the t½ ofCompound A is about 5 hrs to 10 hrs. In some embodiments, t½ is about 5hrs. In some embodiments, t½ is about 6 hrs. In some embodiments, t½ isabout 7 hrs. In some embodiments, t½ is about 8 hrs. In someembodiments, t½ is about 9 hrs In some embodiments, t½ is about 10 hrs.

5. Dosing

In some embodiments of the present methods and uses, Compound A, or apharmaceutically acceptable salt thereof, and/or composition thereof isadministered (e.g., orally) to the patient in need thereof.

In some embodiments, a method of the present disclosure comprises orallyadministering to a patient up to about 10,000 mg of Compound A, or apharmaceutically acceptable salt thereof, for example up to about 500mg, up to about 1,000 mg, up to about 1,500 mg, up to about 2,000 mg, upto about 2,500 mg, up to about 3,000 mg, up to about 3,500 mg, up toabout 4,000 mg, up to about 4,500 mg, up to about 5,000 mg, up to about5,500 mg, up to about 6,000 mg, up to about 6,500 mg, up to about 7,000mg, up to about 7,500 mg, up to about 8,000 mg, up to about 8,500 mg, upto about 9,000 mg, up to about 9,500 mg, or up to about 10,000 mg ofCompound A, or a pharmaceutically acceptable salt thereof, and/orcomposition thereof. In some embodiments, a method of the presentdisclosure comprises administering to a patient about 500-5,000 mg (forexample, about 1,000 to about 4,000 mg, about 1,000 to about 4,000 mg,about 1,000 to about 4,000 mg, about 1,000 to about 4,000 mg, about1,000 to about 4,000 mg, about 1,000 to about 4,000 mg, or about 1,000to about 4,000 mg) of Compound A, or a pharmaceutically acceptable saltthereof, and/or composition thereof. For example, in some embodiments, amethod of the present disclosure comprises administering to a patientabout 3,000 mg of Compound A, or a pharmaceutically acceptable saltthereof, and/or composition thereof, for example in a single 3,000 mgdose. In some embodiments, a method of the present disclosure comprisesadministering daily to a patient about 3,000 mg of Compound A, or apharmaceutically acceptable salt thereof, and/or composition thereof,for example as two 1,500 mg doses. In some embodiments, a method of thepresent disclosure comprises administering daily to a patient about3,000 mg of Compound A, or a pharmaceutically acceptable salt thereof,and/or composition thereof, for example as three 1,000 mg doses. In someembodiments, a method of the present disclosure comprises administeringCompound A, or a pharmaceutically acceptable salt thereof, and/orcomposition thereof as described herein once daily. In some embodiments,a method of the present disclosure comprises administering a Compound A,or a pharmaceutically acceptable salt thereof, and/or compositionthereof as described herein twice daily. In some embodiments, a methodof the present disclosure comprises administering a Compound A, or apharmaceutically acceptable salt thereof, and/or composition thereof asdescribed herein three times daily. In some embodiments, a method of thepresent disclosure comprises administering a Compound A, or apharmaceutically acceptable salt thereof, and/or composition thereof asdescribed herein four to fourteen times daily.

In some embodiments, where the patient is administered daily about 600mg of Compound A, or a pharmaceutically acceptable salt thereof, thedosing is twice daily or BID, i.e., two separate about 300 mg doses. Insome embodiments, where the patient is administered daily about 600 mgof Compound A, or a pharmaceutically acceptable salt thereof, the dosingis thrice daily or TID, i.e., three separate about 200 mg doses. In someembodiments, where the patient is administered daily about 600 mg ofCompound A, or a pharmaceutically acceptable salt thereof, the dosing isfour-times daily or QID, i.e., four separate about 150 mg doses.

In some embodiments, where the patient is administered daily about 800mg of Compound A, or a pharmaceutically acceptable salt thereof, thedosing is twice daily or BID, i.e., two separate about 400 mg doses. Insome embodiments, where the patient is administered daily about 800 mgof Compound A, or a pharmaceutically acceptable salt thereof, the dosingis thrice daily or TID, i.e., three separate about 267 mg doses. In someembodiments, where the patient is administered daily about 800 mg ofCompound A, or a pharmaceutically acceptable salt thereof, the dosing isfour-times daily or QID, i.e., four separate about 200 mg doses.

In some embodiments, where the patient is administered daily about 1000mg of Compound A, or a pharmaceutically acceptable salt thereof, thedosing is twice daily or BID, i.e., two separate about 500 mg doses. Insome embodiments, where the patient is administered daily about 1000 mgof Compound A, or a pharmaceutically acceptable salt thereof, the dosingis thrice daily or TID, i.e., three separate about 333 mg doses. In someembodiments, where the patient is administered daily about 1000 mg ofCompound A, or a pharmaceutically acceptable salt thereof, the dosing isfour-times daily or QID, i.e., four separate about 250 mg doses.

In some embodiments, where the patient is administered daily about 1200mg of Compound A, or a pharmaceutically acceptable salt thereof, thedosing is twice daily or BID, i.e., two separate about 600 mg doses. Insome embodiments, where the patient is administered daily about 1200 mgof Compound A, or a pharmaceutically acceptable salt thereof, the dosingis thrice daily or TID, i.e., three separate about 400 mg doses. In someembodiments, where the patient is administered daily about 1200 mg ofCompound A, or a pharmaceutically acceptable salt thereof, the dosing isfour-times daily or QID, i.e., four separate about 300 mg doses.

In some embodiments, where the patient is administered daily about 1400mg of Compound A, or a pharmaceutically acceptable salt thereof, thedosing is twice daily or BID, i.e., two separate about 700 mg doses. Insome embodiments, where the patient is administered daily about 1400 mgof Compound A, or a pharmaceutically acceptable salt thereof, the dosingis thrice daily or TID, i.e., three separate about 467 mg doses. In someembodiments, where the patient is administered daily about 1400 mg ofCompound A, or a pharmaceutically acceptable salt thereof, the dosing isfour-times daily or QID, i.e., four separate about 350 mg doses.

In some embodiments, where the patient is administered daily about 1600mg of Compound A, or a pharmaceutically acceptable salt thereof, thedosing is twice daily or BID, i.e., two separate about 800 mg doses. Insome embodiments, where the patient is administered daily about 1600 mgof Compound A, or a pharmaceutically acceptable salt thereof, the dosingis thrice daily or TID, i.e., three separate about 533 mg doses. In someembodiments, where the patient is administered daily about 1600 mg ofCompound A, or a pharmaceutically acceptable salt thereof, the dosing isfour-times daily or QID, i.e., four separate about 400 mg doses.

In some embodiments, a method of the present disclosure comprises orallyadministering about 100 mg, about 150 mg, about 200 mg, about 300 mg,about 400 mg, about 500 mg, about 600 mg, about 800 mg, about 1000 mg,about 1200 mg, or about 1400 of Compound A, or a pharmaceuticallyacceptable salt thereof, and/or composition thereof, once a day in asingle dose.

In some embodiments, a method of the present disclosure comprisesadministering a Compound A, or a pharmaceutically acceptable saltthereof, and/or composition thereof as described herein, wherein thereis about 4-24 hours between two consecutive administrations. In someembodiments, there is about 4 hrs, about 6 hrs, about 8 hrs, about 12hrs, about 18 hrs, or about 24 hrs between two consecutiveadministrations.

In some embodiments, a method of the present disclosure comprisesadministering a Compound A, or a pharmaceutically acceptable saltthereof, and/or composition thereof as described herein, wherein thereare about 1-7 days between two consecutive administrations. In someembodiments, there are about 1, about 2, about 3, about 4, about 5,about 6, or about 7 days between two consecutive administrations.

In some embodiments, a method of the present disclosure comprisesadministering a Compound A, or a pharmaceutically acceptable saltthereof, and/or composition thereof as described herein, wherein thereis about 1-4 weeks between two consecutive administrations. In someembodiments, there is about 1, about 2, about 3, or about 4 weeksbetween two consecutive administrations.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated.

6. Pharmaceutically Acceptable Compositions

According to another embodiment, the methods of the present disclosureare practiced by administering a composition comprising Compound A, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this disclosure include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

Compositions of the present disclosure may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this disclosure may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this disclosure may beorally administered in any orally acceptable dosage form including, butnot limited to, capsules, tablets, aqueous suspensions or solutions. Inthe case of tablets for oral use, carriers commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisdisclosure may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this disclosure may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this disclosureinclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this disclosure may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

In certain embodiments, pharmaceutically acceptable compositions of thisdisclosure are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this disclosure areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this disclosure are administered with food.

Pharmaceutically acceptable compositions of this disclosure can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, Compound A may be administered orally at a dose ofabout 10 mg/kg to about 200 mg/kg, particularly at a dose of selectedfrom about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg,about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, and about 90mg/kg, of subject body weight per day, one or more times a day, toobtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of Compound A, it may be desirable toslow the absorption of the compound from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the compound then depends upon its rate of dissolutionthat, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administeredcompound form is accomplished by dissolving or suspending the compoundin an oil vehicle. Injectable depot forms are made by formingmicroencapsule matrices of the compound in biodegradable polymers suchas polylactide-polyglycolide. Depending upon the ratio of compound topolymer and the nature of the particular polymer employed, the rate ofcompound release can be controlled. Examples of other biodegradablepolymers include poly(orthoesters) and poly(anhydrides). Depotinjectable formulations are also prepared by entrapping the compound inliposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisdisclosure with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar—agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

Compound A, or a pharmaceutically acceptable salt thereof, can also bein micro-encapsulated form with one or more excipients as noted above.The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings, release controlling coatings and other coatings well known inthe pharmaceutical formulating art. In such solid dosage forms theactive compound may be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,tableting lubricants and other tableting aids such a magnesium stearateand microcrystalline cellulose. In the case of capsules, tablets andpills, the dosage forms may also comprise buffering agents. They mayoptionally contain opacifying agents and can also be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of embedding compositions that can be used include polymericsubstances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis disclosure include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this disclosure. Additionally, the presentdisclosure contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

7. Methods and Uses for Treating Disease

In some embodiments, the present disclosure provides a method ofadministering Compound A to a patient in need thereof, wherein thepatient suffers from an autoimmune/autoinflammatory disease or ahematological malignancy. In some embodiments, theautoimmune/autoinflammatory disease is a cutaneousautoimmune/autoinflammatory disease.

In some embodiments, the autoimmune/autoinflammatory disease includesinflammatory or allergic conditions of the skin, for example psoriasis,generalized pustular psoriasis (GPP), psoriasis vulgaris, contactdermatitis, atopic dermatitis, alopecia areata, erythema multiforma,dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivityangiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemiclupus erythematosus, pemphigus vulgaris, pemphigus foliaceus,paraneoplastic pemphigus, epidermolysis bullosa acquisita, acnevulgaris, hidradenitis suppurativa, Sweet Syndrome, pyodermagangrenosum, and other inflammatory or allergic conditions of the skin.In some embodiments, the inflammatory disease of the skin is selectedfrom contact dermatitits, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigusvulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysisbullosa acquisita, or hidradenitis suppurativa.

In some embodiments, the Compound A may also be used for the treatmentof other diseases or conditions, such as diseases or conditions havingan inflammatory component, for example, treatment of diseases andconditions of the eye such as ocular allergy, conjunctivitis,keratoconjunctivitis sicca, and vernal conjunctivitis, diseasesaffecting the nose including allergic rhinitis, and inflammatory diseasein which autoimmune reactions are implicated or having an autoimmunecomponent or etiology, including autoimmune hematological disorders(e.g. hemolytic anemia, aplastic anemia, pure red cell anemia andidiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoidarthritis, polychondritis, scleroderma, Wegener granulamatosis,dermatomyositis, chronic active hepatitis, myasthenia gravis,Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory boweldisease (e.g. ulcerative colitis and Crohn's disease), irritable bowelsyndrome, celiac disease, periodontitis, hyaline membrane disease,kidney disease, glomerular disease, alcoholic liver disease, multiplesclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren'ssyndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis,interstitial lung fibrosis, psoriatic arthritis, systemic juvenileidiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis,vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis(with and without nephrotic syndrome, e.g. including idiopathicnephrotic syndrome or minal change nephropathy), chronic granulomatousdisease, endometriosis, leptospiriosis renal disease, glaucoma, retinaldisease, ageing, headache, pain, complex regional pain syndrome, cardiachypertrophy, musclewasting, catabolic disorders, obesity, fetal growthretardation, hyperchlolesterolemia, heart disease, chronic heartfailure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease,incontinentia pigmenti, Paget's disease, pancreatitis, hereditaryperiodic fever syndrome, asthma (allergic and non-allergic, mild,moderate, severe, bronchitic, and exercise-induced), acute lung injury,acute respiratory distress syndrome, eosinophilia, hypersensitivities,anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases,COPD (reduction of damage, airways inflammation, bronchialhyperreactivity, remodeling or disease progression), pulmonary disease,cystic fibrosis, acid-induced lung injury, pulmonary hypertension,polyneuropathy, cataracts, muscle inflammation in conjunction withsystemic sclerosis, inclusion body myositis, myasthenia gravis,thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type2 diabetes, appendicitis, atopic dermatitis, asthma, allergy,blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this disclosure is selected from acute andchronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis,rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenileidiopathic arthritis (SJIA), cryopyrin associated periodic syndrome(CAPS), adult onset Still's disease, macrophage activation syndrome(MAS), primary and secondary hemophagocytic lymphohistiocytosis (HLH),familial Mediterranean fever, NLRP12 autoinflammatory syndrome, andosteoarthritis.

In some embodiments the inflammatory disease which can be treated is aTH17 mediated disease. In some embodiments the TH17 mediated disease isselected from systemic lupus erythematosus, multiple sclerosis,psoriasis vulgaris, hidradenitis suppurativa, and inflammatory boweldisease (including Crohn's disease or ulcerative colitis).

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this disclosure is selected from Sjogren'ssyndrome, allergic disorders, osteoarthritis, conditions of the eye suchas ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernalconjunctivitis, and diseases affecting the nose such as allergicrhinitis or chronic rhinosinusitis with nasal polyps (CRSwNP).

In some embodiments, the present disclosure provides a method fortreating a cutaneous autoimmune/autoinflammatory disease in a patient,such as atopic dermatitis (AD) and hidradenitis suppurativa (HS),comprising administering to the patient a therapeutically effectiveamount of Compound A, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a method fortreating AD in a patient, comprising administering to the patient atherapeutically effective amount of Compound A, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the present disclosure provides a method fortreating HS in a patient, comprising administering to the patient atherapeutically effective amount of Compound A, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the present disclosure provides a method fortreating rheumatoid arthritis (RA) in a patient, comprisingadministering to the patient a therapeutically effective amount ofCompound A, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure provides a method fortreating hematological malignancy in a patient, comprising administeringto the patient a therapeutically effective amount of Compound A, or apharmaceutically acceptable salt thereof. In some embodiments, thehematological malignancy is leukemia, diffuse large B-cell lymphoma(DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chroniclymphocytic lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia(WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma,intravascular large B-cell lymphoma, AML, or MDS.

The following examples are provided for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXEMPLIFICATION

Compound A can be prepared by methods known to one of ordinary skill inthe art, for example, as described in WO 2019/133531 and WO 2020/010227,the contents of which are incorporated herein by reference in theirentireties.

General Abbreviations:

-   -   —    -   Dead animal; no value    -   #, N, No. Number    -   % RSD Relative standard deviation    -   %-Diff Percent difference    -   . No value calculated for mean and standard deviation    -   a.m. Ante meridian    -   API Active pharmaceutical ingredient    -   BID, bid Twice a day    -   BODYTEMP; Btemp Body temperature    -   C Comment found at the end of each group for each sex    -   CAM Covariate-adjusted mean    -   CANFDAS Canned food assessment    -   CO Clinical observation    -   CTLS, ctls Controls    -   CV Coefficient of variation    -   DIA Diastolic pressure    -   DESQUAM Desquamation    -   DSNG Dosing phase    -   DSNG X.X Dosing Phase Week X. Day X    -   DT TY Data type    -   EP European Pharmacopeia    -   F Female    -   FECBOL Number of fecal boli    -   FGSA Forelimb grip strength average (2 trials)    -   FISSUR Fissuring    -   FOOT1 Foot splay 1    -   FOOT2 Foot splay 2    -   FORE1 Forelimb grip strength 1    -   FORE2 Forelimb grip strength 2    -   FSA2 Foot splay average (2 trials)    -   GROOM Number of Grooms    -   HGSA2 Hindlimb grip strength average (2 trials)    -   HIND1 Hindlimb grip strength 1    -   HIND2 Hindlimb grip strength 2    -   ID Identification    -   IM Intramuscular    -   int Interval    -   IPD Immediate postdose    -   LAT Latency    -   LOQ Limit of quantitation    -   M Male    -   MAP Mean arterial pressure    -   Mean; MEAN Arithmetic mean    -   N Number of measurements in a group    -   NA No value; not applicable; not present    -   ND None detected    -   NF National Formulary    -   NVL No visible lesions    -   Obs Observations    -   OD Right eye    -   OS Left eye    -   OU Both eyes    -   OXSA Blood oxygen saturation    -   P Present    -   P(DR) P value (dose response)    -   P(overall) Overall P value for all groups    -   P(vl) P value (versus group 1)    -   p.m. Post meridian    -   PD Postdose    -   PRED Predose phase    -   PRED X.X Predose Phase Week X. Day X    -   RBW Rodent Body Weight    -   REAR Number of rears    -   RECO Recovery phase    -   RECO X.X Recovery Phase Week X. Day X    -   RESP Respiration rate    -   S.E.M./SEM Standard error mean    -   SD; S.D.; STAND Standard deviation (when used in numerical data        tables)    -   DEV; STANDARD    -   DEV; sd; STD.DE    -   SE; STDERR Standard error    -   SYS Systolic pressure    -   TBW Terminal body weight    -   TK Toxicokinetic    -   Typ Type    -   UNSCHED or Unscheduled or scheduled    -   SCHED    -   URIPOL Number of urine pools    -   USP United States Pharmacopeia    -   WK Week    -   WT Weight

Units of Measure:

-   -   amol Attomole    -   BPM Beats per minute    -   ° C. Degrees Celsius    -   cm Centimeter    -   DL, dl, dL Deciliter    -   EU Ehrlich unit    -   FL, fl Femtoliter    -   fmol Femtomole    -   G, g Gram    -   H, h, hr Hours    -   IU International unit    -   KG, kg Kilogram    -   L Liter    -   MCG, UG, μg, ug Microgram    -   MEQ Milliequivalent    -   MG, mg Milligram    -   MI Million    -   ML, mL, ml Milliliter    -   mm Millimeter    -   mmHG/mmHg Millimeter of mercury    -   MMOL, mmol Millimole    -   MN, min Minute    -   MOS Milliosmole    -   Msec, msec Millisecond    -   mU Milliunit    -   ng Nanogram    -   PG, pg Picogram    -   pmol Picomole    -   PPM, ppm Parts per million    -   S, s, sec Seconds    -   TH Thousand    -   U Units    -   UL, μL, uL Microliter    -   UMOL, pmol Micromole    -   um, μm Micrometer

Veterinary Abbreviations

-   -   A Assessment    -   AU Auris utraque (both ears)    -   AWCM Animal Welfare and Comparative Medicine    -   BAR Bright, alert, and responsive    -   BCS Body condition score    -   BW Body weight    -   CRT Capillary refill time    -   DLAM Department of Laboratory Animal Medicine    -   FC Food consumption    -   HC Hydrocortisone    -   IM Intramuscular    -   IV Intravenous    -   NHP Nonhuman primate    -   NSAID Nonsteroidal anti-inflammatory drug    -   MM Mucous membranes    -   P Plan    -   QAR Quiet, alert, and responsive    -   QFC Qualitative food consumption    -   RR Respiration rate    -   SC Subcutaneous    -   SD Study Director (when used in textual data tables)    -   S/O Subjective/objective observations    -   SOAP Subjective/objective observations, assessment, plan    -   TA Test article    -   TM Test article/material    -   TX Treatment    -   VS Veterinary Services    -   WNL Within normal limits

Toxicokinetic Parameters

-   -   C_(max) Maximum observed concentration    -   DN C_(max) Dose-normalized maximum concentration, calculated as        C_(max)/dose    -   T_(max) Time of maximum observed concentration    -   AUC_(0-t) Area under the curve from time 0 to the time of the        last measurable concentration, calculated using the linear        trapezoidal rule    -   AUC₀₋₂₄ Area under the curve from time 0 to 24 hours, calculated        using the linear trapezoidal rule    -   DN AUC₀₋₂₄ Dose-normalized AUC₀₋₂₄, calculated as AUC₀₋₂₄/dose    -   AUC_(0-inf) Area under the curve from time 0 to infinity (Day 1        only), calculated as AUC_(0-inf)=AUC_(0-t)+Ct/λz, where Ct was        the last observed quantifiable concentration and λz was the        elimination rate constant    -   t_(1/2) Elimination half-life, calculated as ln(2)/λz    -   AR Accumulation ratio, calculated as (Day 8, 28, or 42 C_(max)        or AUC₀₋₂₄)/(Day 1 or 15 C_(max) or AUC₀₋₂₄)    -   I.P Isomer to Parent ratio, calculated as (Isomer C_(max) or        AUC₀₋₂₄)/(Parent C_(max) or AUC₀₋₂₄)

Example 1. 4-Week Oral Gavage Toxicity and Toxicokinetic Study withCompound a in Dogs with a 2-Week Recovery

The purpose of this study was to evaluate the toxicity and determine theToxicokinetics (TK) of the test article, Compound A, when administeredonce daily via oral gavage to dogs for up to 4 weeks and to assess thereversibility of any effects after a 2-week recovery. Animals wereinitially administered 5, 30, 200, or 100 mg/kg/dose (originally, onlyTK collections), with the 200 mg/kg/day dose level reduced to 60mg/kg/day (200/60 mg/kg/dose) from Days 15 through 42.

Male and female dogs were assigned to five groups, and doses wereadministered as indicated in Table 1. Animals were dosed via oral gavageonce daily, for up to 28 days, up to a volume of 5 mL/kg. The controlarticle was 25% (w/w) Hydroxypropyl-β-cyclodextrin (HPBCD; Kleptose OralGrade HPB) prepared in reverse osmosis water; pH 3.5±0.1. The vehiclewas HPBCD (Kleptose Oral Grade HPB) prepared in reverse osmosis water.

TABLE 1 Dose administration. Does Con- No. of Animals^(b) Dose Level^(c)centration^(d. e) Group^(a) Male Female (mg/kg/dose) (mg/mL) 1 (Control)5 5 0 0 2 (Low) 3 3 5 1/2 3 (Mid) 5 5 30  6/12 4 (High) 5 5 200/60 40/245 (Mid-High) 3 3 100 20/20 ^(a)Group 1 were administered control articleonly. Group 5 animals were sacrificed on Day 11 of the dosing phase.^(b)Animals designated for recovery sacrifice (two animals/sex/group inGroups 1, 3, and 4) underwent 2 weeks of recovery following doseadministration. ^(c)On Days 1 through 8, doses were administered toanimals in Group 4 at a level of 200 mg/kg/dose. Starting on Day 15,doses were administered to animals in Group 4 at a level of 60mg/kg/dose. ^(d)Concentrations were corrected for potency using acorrection factor of 5.1813. ^(e)On Days 1 through 8, doses wereadministered to animals in all Groups at a volume of 5 mL/kg. Startingon Day 9, doses were administered to all animals in Groups 1, 2, and 3at a volume of 2.5 mL/kg. Starting on Day 15, doses were administered toall animals in Group 4 at a volume of 2.5 mL/kg. On Day 9, dosescontinued to be administered to animals in Group 5 at a volume of 5mL/kg.

Assessment of toxicity was based on mortality, clinical observations,body weights, food consumption, ophthalmic observations,electrocardiographic (ECG) measurements, and clinical and anatomicpathology. Blood samples were collected for toxicokinetic evaluation.

Results

All formulations from Days 1, 28, and 42 were within 10% of the targetconcentration (ranging from 96.5 to 103.0% of the theoreticalconcentration, with a relative standard deviation ranging from 0.5 to1.7%).

Samples for dose analysis from the formulations prepared for dosing onDays 9 and 15 of the dosing phase were not collected, which was aProtocol deviation. It is expected that the formulations prepared onDays 9 and 15 also met specifications, as the results of theformulations prepared for dosing on Days 1, 28, and 42 all metspecifications.

All formulations analyzed met the acceptance criteria for study use, andanimals were administered the intended dose.

All concentration values of Compound A, Compound B, and Compound C inthe vehicle control group were below the lower limit of quantitation(<1.00 ng/mL).

Sex differences in Compound A, Compound B, and Compound C mean C_(max)and AUC₀₋₂₄ values were less than 2-fold; therefore, results anddiscussion were based on combined sex values.

Toxicokinetics of Compound A

After oral gavage administration, Compound A was absorbed, with medianT_(max) values ranging from 5.00 to 9.00 hours on Day 1, from 5.00 to12.0 hours on Day 8, 6.00 hours on Day 15 (Group 4 only), 4.00 hours onDay 28 (Groups 2 and 3 only), and 6.00 hours on Day 42 (Group 4 only).After reaching C_(max), Compound A concentrations declined, with meanhalf-life (t_(1/2)) values ranging from 6.54 to 7.60 hours on Day 1,8.08 hours on Day 8, and 8.19 hours on Day 28. Due to the lack of adistinct elimination phase, estimation of elimination phase half-life(t_(1/2)) was not attempted for most profiles. Mean concentration valuesfor Compound A were measurable through 24 hours postdose on allcollection intervals.

The mean concentration-time profiles for combined sexes show that meanconcentrations of Compound A increased with the increase in dose levelfrom 5 to 100 mg/kg/dose on Days 1 and 8 and from 5 to 30 mg/kg/dose onDay 28. No increase in exposure was observed with a further increase indose level from 100 to 200 mg/kg/dose on Days 1 and 8. Meanconcentrations of Compound A were generally similar after multiple doseswhen compared to a single dose.

Exposure, as assessed by Compound A mean C_(max) and AUC₀₋₂₄ values,increased with the increase in Compound A dose level from 5 to 100mg/kg/dose on Days 1 and 8, and from 5 to 30 mg/kg/dose on Day 28. Noincrease in exposure was observed with a further increase in dose levelfrom 100 to 200 mg/kg/dose on Days 1 and 8. The increases in Compound Amean C_(max) and AUC₀₋₂₄ values were less than dose proportional.

Compound A mean C_(max) and AUC₀₋₂₄ values were generally higher on Days8 and 28 when compared to Day 1 at the 30 and 100 mg/kg/dose levels, asapplicable, indicating potential accumulation of Compound A aftermultiple doses in dogs. On Day 8, mean accumulation ratio values rangedfrom 1.16 to 1.86 for C_(max) and from 1.12 to 2.14 for AUC₀₋₂₄. On Day28, mean accumulation ratio values were 1.38 and 1.28 for C_(max) andAUC₀₋₂₄, respectively, for Group 2 and 1.96 and 2.12 for C_(max) andAUC₀₋₂₄, respectively, for Group 3.

TABLE 2 Summary of Compound A Toxicokinetic Parameters in Dog PlasmaCmpd A Dose Dose Level C_(max) AUC₀₋₂₄ Day Group (mg/kg/dose) (ng/mL)T_(max) (h) (h * ng/mL) t_(1/2) 1 2 5 83.3 5 1390 7.60 3 30 292 6 48806.54ª 4 200 351 6 7190 NR 5 100 363 9 7080 NR 8 2 5 107 5 1720 8.08 3 30496 5 10500 NR 4 200 531 12 12000 NR 5 100 640 12 14300 NR 15 4 60 489 610200 NR 28 2 5 123 4 1990 8.19 3 30 569 4 10500 NR 42 4 60 561 6 11700NR NR = Not reported due to the lack of a distinct elimination phase.Note: Median values are presented for T_(max). ^(a)Represents N = 1

Toxicokinetics of Compound B

After oral gavage administration of Compound A, Compound B appeared inplasma, with median T_(max) values ranging from 6.00 to 9.00 hours onDay 1, and 4.00 hours on Days 8, 15 (Group 4 only), 28 (Groups 2 and 3only), and 42 (Group 4 only). After reaching C_(max), Compound Bconcentrations declined, with mean t_(1/2) values of 7.60, 8.18, and8.19 hours on Days 1, 8, and 28, respectively, for Group 2. Due to thelack of a distinct elimination phase, estimation of elimination phaset_(1/2) was not attempted for most profiles. Mean concentration valuesfor Compound B were measurable through 24 hours postdose on allcollection intervals.

Mean concentrations of Compound B generally increased with the increasein Compound A dose level from 5 to 100 mg/kg/dose on Days 1 and 8, andfrom 5 to 30 mg/kg/dose on Day 28. No increase in exposure was observedwith a further increase in dose level from 100 to 200 mg/kg/dose on Days1 and 8. Mean concentrations of Compound B were generally similar aftermultiple doses of Compound A when compared to a single dose.

Exposure, as assessed by Compound B mean C_(max) and AUC₀₋₂₄ values,increased with the increase in Compound A dose level from 5 to 100mg/kg/dose on Days 1 and 8, and from 5 to 30 mg/kg/dose on Day 28. Noincrease in exposure was observed with a further increase in dose levelfrom 100 to 200 mg/kg/dose on Days 1 and 8. The increases in Compound Bmean C_(max) and AUC₀₋₂₄ values were less than dose proportional.

Compound B mean C_(max) and AUC₀₋₂₄ values were generally were generallyhigher on Days 8 and 28 when compared to Day 1 at the 30 and 100mg/kg/dose levels, as applicable, indicating potential accumulation ofCompound B after multiple doses in dogs. On Day 8, mean accumulationratio values were 1.10 to 1.07 for C_(max) and AUC₀₋₂₄, respectively,for Group 2 and 1.70 and 1.93 for C_(max) and AUC₀₋₂₄, respectively forGroup 3. On Day 28, mean accumulation ratio values were 1.40 and 1.32for C_(max) and AUC₀₋₂₄ for Groups 2 and 3, respectively, and 1.81 and1.98 for C_(max) and AUC₀₋₂₄, respectively, for Group 3.

On Day 1, the mean Compound B isomer to parent ratios ranged from 0.621to 0.677 for C_(max) and from 0.605 to 0.712 for AUC₀₋₂₄. On Day 8, themean isomer to parent ratios ranged from 0.584 to 0.613 for C_(max) andfrom 0.571 to 0.595 for AUC₀₋₂₄. On Day 15, the mean isomer to parentratios were 0.551 for C_(max) and 0.542 for AUC₀₋₂₄ for Group 4. On Day28, the mean isomer to parent ratios were 0.630 and 0.623 for C_(max)and AUC₀₋₂₄, respectively, for Group 2 and 0.578 and 0.629 for C_(max)and AUC₀₋₂₄, respectively, Group 3. On Day 42, the mean isomer to parentratios were 0.509 for C_(max) and 0.513 for AUC₀₋₂₄ for Group 4.

TABLE 3 Summary of Compound B Toxicokinetic Parameters in Dog PlasmaCmpd A Dose Dose Level C_(max) AUC₀₋₂₄ Day Group (mg/kg/dose) (ng/mL)T_(max) (h) (h * ng/mL) t_(1/2) 1 2 5 51.7 6 834 7.60 3 30 177 6 3170 NR4 200 228 9 4720 NR 5 100 246 6 5010 NR 8 2 5 63.4 4 1010 8.18 3 30 3034 6200 NR 4 200 311 4 6830 NR 5 100 372 4 8170 NR 15 4 60 269 4 5490 NR28 2 5 77.7 4 1250 8.19 3 30 326 4 6500 NR 42 4 60 288 4 6090 NR NR =Not reported due to the lack of a distinct elimination phase. Note:Median values are presented for T_(max). ^(a) Represents N = 1

Toxicokinetics of Compound C

After oral gavage administration of Compound A, Compound C appeared inplasma, with a median T_(max) value of 6.00 hours on Day 1 and 4.00hours on Days 8, 15 (Group 4 only), 28 (Groups 2 and 3 only), and 42(Group 4 only). After reaching C_(max), Compound C concentrationsdeclined, with mean t_(1/2) values ranging from 7.65, 9.11, and 8.06hours on Days 1, 8, and 28, respectively, for Group 2. Due to the lackof a distinct elimination phase, estimation of elimination phase t_(1/2)was not attempted for most profiles. Mean concentration values forCompound C were measurable through 24 hours postdose on all collectionintervals.

Mean concentrations of Compound C generally increased with the increasein Compound A dose level from 5 to 100 mg/kg/dose on Days 1 and 8, andfrom 5 to 30 mg/kg/dose on Day 28. No increase in exposure was observedwith a further increase in dose level from 100 to 200 mg/kg/dose on Days1 and 8. Mean concentrations of Compound C were generally similar aftermultiple doses of Compound A when compared to a single dose.

Exposure, as assessed by Compound C mean C_(max) and AUC₀₋₂₄ values,increased with the increase in Compound A dose level from 5 to 100mg/kg/dose on Days 1 and 8, and from 5 to 30 mg/kg/dose on Day 28. Noincrease in exposure was observed with a further increase in dose levelfrom 100 to 200 mg/kg/dose on Days 1 and 8. The increases in Compound Cmean C_(max) and AUC₀₋₂₄ values were less than dose proportional.

Compound C mean C_(max) and AUC₀₋₂₄ values were generally were generallyhigher on Days 8 and 28 when compared to Day 1 at the 30 and 100mg/kg/dose levels, as applicable, indicating potential accumulation ofCompound C after multiple doses in dogs. On Day 8, mean accumulationratio values ranged from 1.11 to 1.63 for C_(max) and from 1.11 to 1.79for AUC₀₋₂₄. On Day 28, mean accumulation ratio values were 1.45 and1.36 for C_(max) and AUC₀₋₂₄, respectively for Group 2 and 1.73 and 1.86for C_(max) and AUC₀₋₂₄, respectively, for Group 3.

On Day 1, the mean Compound C isomer to parent ratios ranged from 0.584to 0.635 for C_(max) and from 0.597 to 0.655 for AUC₀₋₂₄. On Day 8, themean isomer to parent ratios ranged from 0.508 to 0.584 for C_(max) andfrom 0.504 to 0.574 for AUC₀₋₂₄.

On Day 15, the mean isomer to parent ratios were 0.521 for C_(max) and0.509 for AUC₀₋₂₄ for Group 4. On Day 28, the mean isomer to parentratios were 0.651 and 0.636 for C_(max) and AUC₀₋₂₄, respectively, forGroup 2 and 0.527 and 0.571 for C_(max) and AUC₀₋₂₄, respectively, forGroup 3. On Day 42, the mean isomer to parent ratios were 0.476 forC_(max) and 0.481 for AUC₀₋₂₄ for Group 4.

TABLE 4 Summary of Compound C Toxicokinetic Parameters in Dog PlasmaCmpd A Dose Dose Level C_(max) AUC₀₋₂₄ Day Group (mg/kg/dose) (ng/mL)T_(max) (h) (h * ng/mL) t_(1/2) 1 2 5 50.9 6 800 7.65ª 3 30 166 6 3040NR 4 200 222 6 4510 NR 5 100 231 6 4650 NR 8 2 5 59.8 4 952 9.11 3 30273 4 5480 NR 4 200 271 4 5970 NR 5 100 325 4 7210 NR 15 4 60 245 4 4980NR 28 2 5 77.7 4 1190 8.06 3 30 290 4 5790 NR 42 4 60 265 4 5620 NR NR =Not reported due to the lack of a distinct elimination phase. Note:Median values are presented for T_(max). ^(a)Represents N = 1

Sex differences in Compound A, Compound B, and Compound C mean C_(max)and AUC₀₋₂₄ values were less than 2-fold. Exposure, as assessed byCompound A, Compound B, and Compound C mean C_(max) and AUC₀₋₂₄ values,increased with the increase in Compound A dose level from 5 to 100mg/kg/dose on Days 1 and 8, and from 5 to 30 mg/kg/dose on Day 28. Noincrease in exposure was observed with a further increase in dose levelfrom 100 to 200 mg/kg/dose on Days 1 and 8. The increases in Compound A,Compound B, and Compound C mean C_(max) and AUC₀₋₂₄ were less than doseproportional. Potential accumulation of Compound A, Compound B, andCompound C, up to 2.14-, 1.98-, and 1.86-fold, respectively, wasobserved after multiple doses in dogs.

During Days 1 to 8 of the dosing phase, abnormal fecal observations andbody weight loss were noted across all groups, including controls, andthese observations were likely due to the high concentration (25%) ofHPBCD in the formulations. The incidence of abnormal fecal observationswas reduced following the dose volume reduction from Day 9 of the dosingphase. Therefore, these observations were considered not Compound Arelated.

One female administered 100 mg/kg/dose was sacrificed in a moribundcondition on Day 4 of the dosing phase with clinical observations ofdecreased activity, liquid feces, vomitus, dehydration, and tremors; thedeath of this animal was considered test article related. ObviousCompound A-related organ toxicity was not identified in the unscheduledclinical pathology data collected at the unscheduled interval, andchanges (compared with predose phase results) were likely secondary tothe clinical moribund condition of the animal (potentialhypotension/shock). No macroscopic or microscopic findings were notedthat determined the cause of the moribund condition. Slightly tomoderately increased lymphocyte apoptosis in all lymphoid tissues wereconsistent with a stress response rather than a direct effect ofCompound A. All animals administered 100 mg/kg/dose were sacrificed onDay 11 of the dosing phase.

The test article-related mortality on Day 4 of the dosing phase for onefemale administered 100 mg/kg/dose and similar clinical observations(emesis, fecal abnormalities, decreased activity, lower foodconsumption, and tremors) noted in animals administered >100 mg/kg/doseexceeded a maximum tolerated dose. This resulted in the sacrifice on Day11 of the dosing phase of all animals administered 100 mg/kg/dose (whichwere originally designated for only TK collections) and high-doseanimals (200 mg/kg/dose) having a 1-week dose suspension before resumingdosing at 60 mg/kg/dose for four weeks. The clinical observationsresolved in the animals administered 200 mg/kg/dose during the dosesuspension period.

All other animals survived to their scheduled sacrifice.

No Compound A-related clinical observations or abnormal ophthalmicobservations were noted. No Compound A-related alterations in mean bodyweight, body weight gain, or food consumption were noted at any doselevel. No Compound A-related abnormalities were noted during the dosingphase ECG observation.

No Compound A-related effects in scheduled hematology, coagulation,clinical chemistry, or urinalysis test results were identified.

No Compound A-related organ weight differences or macroscopicobservations were noted.

At the unscheduled early termination and terminal sacrifice, CompoundA-related microscopic findings included minimal or slight infiltrates ofvacuolated macrophages in the lamina propria of the jejunum and ileum ofanimals administered ≥30 mg/kg/dose and in the duodenum of animalsadministered 200/60 mg/kg/dose and in one female administered 100mg/kg/dose. Minimally or slightly increased infiltrates of vacuolatedmacrophages in the gut-associated lymphoid tissues (GALT)/Peyer'spatches of animals administered ≥5 mg/kg/dose and in the mesenteric andmandibular lymph nodes and spleen of animals administered ≥30 mg/kg/dosewere also considered Compound A related. In the lung, Compound A-relatedminimal increases of vacuolated alveolar macrophages were observed inanimals administered ≥30 mg/kg/dose. The Compound A-related increases ofvacuolated macrophages in the small intestine, lymphoid tissues, andlung were considered nonadverse due to the low severity and lack ofassociated degenerative or inflammatory changes. This cytoplasmicvacuolation was consistent with phospholipidosis as demonstrated by theultrastructural (transmission electron microscopy) finding of whorledlamellar bodies (interpreted as myelin figures) within secondarylysosomes in the lung, mesenteric lymph node, and ileum of dogsadministered 100 mg/kg/dose Compound A in a prior 2-week oral toxicityand toxicokinetics study (Charles River 20.345; Charles RiverLaboratories, Inc., 2020).

Slight degeneration (bilateral) of seminiferous tubules in the testeswith associated increased cell debris in the epididymides was noted inone peripubertal male administered 200/60 mg/kg/dose. The relationshipof this testicular finding to administration of Compound A was unclearsince degeneration, exfoliation, and depletion of testicular germinalepithelial cells can be observed in the testes of dogs at this stage ofsexual maturity (Lanning et al., 2002) and the incidence of testiculardegeneration in this study was within the historical control range forthis laboratory.

At the recovery sacrifice, minimal vacuolated macrophages in the smallintestine (jejunum and/or ileum), GALT/Peyer's patches, and mandibularlymph nodes of animals administered 30 or 200/60 mg/kg/dose andminimally increased vacuolated macrophages in the lung of one maleadministered 200/60 mg/kg/dose indicating partial reversal. No increasesof vacuolated macrophages were noted in the spleen at either dose level,indicating complete reversal. Minimally or moderately increasedinfiltrates of vacuolated macrophages in the mesenteric lymph node ofone male administered 200/60 mg/kg/dose and females administered 30 or200/60 mg/kg/dose suggested a lack of reversal after 2 weeks.

In conclusion, male and female beagles were administered control articleor Compound A via oral gavage at 100 mg/kg/dose for 10 days, 5 and 30mg/kg/dose Compound A for 4 weeks, and 200 mg/kg/dose for one weekfollowed by one week dose suspension and then resuming dosing at 60mg/kg/dose for 4 weeks. The dose level of 60 mg/kg/day was determined tobe the no observed adverse effect level (NOAEL) based on no clear oradverse test article-related findings in animals that had beenpreviously dosed for 10 days at 200 mg/kg/dose. The dose levels of 100and 200 mg/kg/dose were considered adverse due to the mortality at 100mg/kg/dose, while the 200 mg/kg/dose formulation was not tolerated andnecessitated a dose suspension and dose reduction. The dose level of 60mg/kg/dose corresponded to average, sex-combined, maximum observedconcentration (C_(max)) and area under the concentration-time curve(AUC₀₋₂₄) values of 561 ng/mL and 11,700 ng*hr/mL, respectively forCompound A; 288 ng/mL and 6090 ng*hr/mL, respectively, for Compound B;and 265 ng/mL and 5620 ng*hr/mL, respectively, for Compound C on Day 42of the dosing phase.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the application and claims rather than by the specificembodiments that have been represented by way of example.

1. A method of treating an autoimmune/autoinflammatory disease and/or ahematological malignancy, comprising administering to a patient in needthereof a therapeutically effective amount of Compound A, or apharmaceutically acceptable salt thereof, and/or composition thereof,wherein a C_(max) of up to about 561 ng/mL of Compound A in plasma isachieved, and wherein Compound A is5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.2. The method of claim 1, wherein the C_(max) of Compound A in plasma isabout 500 ng/mL to about 561 ng/mL.
 3. The method of claim 1 or 2,wherein the C_(max) of Compound A in plasma is about 450 ng/mL to about550 ng/mL.
 4. The method of any one of claims 1 to 3, wherein a C_(max)of up to about 288 ng/mL of Compound B in plasma is achieved, whereinCompound B is5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-((S)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.5. The method of claim 4, wherein the C_(max) of Compound B in plasma isabout 260 ng/mL to about 288 ng/mL.
 6. The method of claim 4 or 5,wherein the C_(max) of Compound B in plasma is about 240 ng/mL to about260 ng/mL.
 7. The method of any one of claims 1 to 6, wherein a C_(max)of up to about 265 ng/mL of Compound C in plasma is achieved, whereinCompound C is5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-((R)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.8. The method of claim 7, wherein the C_(max) of Compound C in plasma isabout 240 ng/mL to about 265 ng/mL.
 9. The method of claim 7 or 8,wherein the C_(max) of Compound C in plasma is about 220 ng/mL to about240 ng/mL.
 10. The method of any one of claims 1-9, wherein the CompoundA is administered at a dose of about 10 mg/kg to about 200 mg/kg. 11.The method of claim 10, wherein the Compound A is administered at a doseselected from the group consisting of about 30 mg/kg, about 35 mg/kg,about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg,about 85 mg/kg, and about 90 mg/kg.
 12. A method of treating anautoimmune/autoinflammatory disease and/or a hematological malignancy,comprising administering to a patient in need thereof a therapeuticallyeffective amount of Compound A, or a pharmaceutically acceptable saltand/or composition thereof, wherein an AUC₀₋₂₄ of up to about 11700ng*hr/mL of Compound A in plasma is achieved, and wherein Compound A is5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.13. The method of claim 12, wherein the AUC₀₋₂₄ of Compound A in plasmais about 11,000 ng*h/mL to about 11,700 ng*h/mL.
 14. The method of claim12 or 13, wherein the AUC₀₋₂₄ of Compound A in plasma is about 10,000ng*h/mL to about 11,000 ng*h/mL.
 15. The method of any one of claim 12to 14, wherein an AUC₀₋₂₄ of up to about 6090 ng*h/mL of Compound B inplasma is achieved, and wherein Compound B is5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-((S)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.16. The method of claim 15, wherein the AUC₀₋₂₄ of Compound B in plasmais about 5500 ng*h/mL to about 6090 ng*h/mL.
 17. The method of claim 15or 16, wherein the AUC₀₋₂₄ of Compound B in plasma is about 5,000ng*h/mL to about 5500 ng*h/mL.
 18. The method of any one of claim 12 to17, wherein an AUC₀₋₂₄ of up to about 5620 ng*h/mL of Compound C inplasma is achieved, and wherein Compound B is5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-((R)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide.19. The method of claim 18, wherein the AUC₀₋₂₄ of Compound C in plasmais about 5000 ng*h/mL to about 5620 ng*h/mL.
 20. The method of claim 18or 19, wherein the AUC₀₋₂₄ of Compound C in plasma is about 4500 ng*h/mLto about 5,000 ng*h/mL.
 21. The method of any one of claims 12 to 20,wherein Compound A is administered at a dose of about 10 mg/kg to about200 mg/kg.
 22. The method of any one of claims 12 to 21, whereinCompound A is administered at a dose selected from about 30 mg/kg, about35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg,about 80 mg/kg, about 85 mg/kg, and about 90 mg/kg.
 23. The method ofany one of claims 1 to 22, wherein the T_(max) of Compound A is achievedin about 4 hrs to 12 hrs.
 24. The method of any one of claims 1 to 23,wherein the autoimmune/autoinflammatory disease is selected from acutaneous, rheumatic, and gastrointestinal autoimmune/autoinflammatorydisease.
 25. The method of any one of claims 1 to 23, wherein theautoimmune/autoinflammatory disease is a cutaneousautoimmune/autoinflammatory disease selected from atopic dermatitis (AD)and hidradenitis suppurativa (HS).